Behavioral changes and brain epigenetic alterations induced by maternal deficiencies of B vitamins in a mouse model.

RATIONALE: B vitamins play essential roles in brain development and functionality; however, the effects of their deficiency during early life on mental health are not thoroughly understood. OBJECTIVES: The objective of this study is to investigate the effects of a maternal deficiency of vitamin B6, B9 (folate), and B12 on behavioral changes in adult offspring. METHODS: Female C57BL/6 J mice were put on a diet lacking vitamin B6, B9, B12, or the above three vitamins from pregnancy to weaning. The growth and developmental characteristics of both the pregnant mothers and offspring were collected. In the adult offspring, the serum levels of neuroactive substances were measured using an enzyme-linked immunosorbent assay. The level of BDNF and dimethylated lysine 9 on histone H3 (H3K9me2) was detected by immunohistochemical staining. In addition, their depressive-like behaviors, anxiety-like behaviors, and sociability were recorded using sucrose preference, a forced swim, social interaction, tail suspension, and open field tests. RESULTS: The maternal deficiency of the three B vitamins delayed offspring development. Compared to the controls, all of the groups showed decreased serum levels of 5-HT and neuropeptide Y. In the groups with deficiency of B9 or the three B vitamins, there were significant changes in sociability and social novelty preference. In groups with deficiencies in B9, B12, or all three B vitamins, the expression levels of BDNF and H3K9me2 in the hippocampus were significantly decreased. CONCLUSIONS: Maternal deficiencies of the major B vitamins caused changes in social behaviors in adult mice accompanied with epigenetic alterations in the brain and changes in the serum levels of neuroactive substances.

Gut microbiota-derived vitamins - underrated powers of a multipotent ally in psychiatric health and disease.

Despite the well-established roles of B-vitamins and their deficiencies in health and disease, there is growing evidence indicating a key role of those nutrients in functions of the central nervous system and in psychopathology. Clinical data indicate the substantial role of B-vitamins in various psychiatric disorders, including major depression, bipolar disorder, schizophrenia, autism, and dementia, including Alzheimer's and Parkinson's diseases. As enzymatic cofactors, B-vitamins are involved in many physiological processes such as the metabolism of glucose, fatty acids and amino acids, metabolism of tryptophan in the kynurenine pathway, homocysteine metabolism, synthesis and metabolism of various neurotransmitters and neurohormones including serotonin, dopamine, adrenaline, acetylcholine, GABA, glutamate, D-serine, glycine, histamine and melatonin. Those vitamins are highly involved in brain energetic metabolism and respiration at the cellular level. They have a broad range of anti-inflammatory, immunomodulatory, antioxidant and neuroprotective properties. Furthermore, some of those vitamins are involved in the regulation of permeability of the intestinal and blood-brain barriers. Despite the fact that a substantial amount of the above vitamins is acquired from various dietary sources, deficiencies are not uncommon, and it is estimated that micronutrient deficiencies affect about two billion people worldwide. The majority of gut-resident microbes and the broad range of bacteria available in fermented food, express genetic machinery enabling the synthesis and metabolism of B-vitamins and, consequently, intestinal microbiota and fermented food rich in probiotic bacteria are essential sources of B-vitamins for humans. All in all, there is growing evidence that intestinal bacteria-derived vitamins play a significant role in physiology and that dysregulation of the "microbiota-vitamins frontier" is related to various disorders. In this review, we will discuss the role of vitamins in mental health and explore the perspectives and potential of how gut microbiota-derived vitamins could contribute to mental health and psychiatric treatment.

Impact of Hyperhomocysteinemia and Different Dietary Interventions on Cognitive Performance in a Knock-in Mouse Model for Alzheimer's Disease.

BACKGROUND: Hyperhomocysteinemia is considered a possible contributor to the complex pathology of Alzheimer's disease (AD). For years, researchers in this field have discussed the apparent detrimental effects of the endogenous amino acid homocysteine in the brain. In this study, the roles of hyperhomocysteinemia driven by vitamin B deficiency, as well as potentially beneficial dietary interventions, were investigated in the novel AppNL-G-F knock-in mouse model for AD, simulating an early stage of the disease. METHODS: Urine and serum samples were analyzed using a validated LC-MS/MS method and the impact of different experimental diets on cognitive performance was studied in a comprehensive behavioral test battery. Finally, we analyzed brain samples immunohistochemically in order to assess amyloid-ß (Aß) plaque deposition. RESULTS: Behavioral testing data indicated subtle cognitive deficits in AppNL-G-F compared to C57BL/6J wild type mice. Elevation of homocysteine and homocysteic acid, as well as counteracting dietary interventions, mostly did not result in significant effects on learning and memory performance, nor in a modified Aß plaque deposition in 35-week-old AppNL-G-F mice. CONCLUSION: Despite prominent Aß plaque deposition, the AppNL-G-F model merely displays a very mild AD-like phenotype at the investigated age. Older AppNL-G-F mice should be tested in order to further investigate potential effects of hyperhomocysteinemia and dietary interventions.

Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence.

Vitamins and minerals are essential to humans as they play essential roles in a variety of basic metabolic pathways that support fundamental cellular functions. In particular, their involvement in energy-yielding metabolism, DNA synthesis, oxygen transport, and neuronal functions makes them critical for brain and muscular function. These, in turn, translate into effects on cognitive and psychological processes, including mental and physical fatigue. This review is focused on B vitamins (B1, B2, B3, B5, B6, B8, B9 and B12), vitamin C, iron, magnesium and zinc, which have recognized roles in these outcomes. It summarizes the biochemical bases and actions of these micronutrients at both the molecular and cellular levels and connects them with cognitive and psychological symptoms, as well as manifestations of fatigue that may occur when status or supplies of these micronutrients are not adequate.

A Systematic Review and Meta-Analysis of B Vitamin Supplementation on Depressive Symptoms, Anxiety, and Stress: Effects on Healthy and 'At-Risk' Individuals.

A systematic review and meta-analysis was undertaken to examine and quantify the effects of B vitamin supplementation on mood in both healthy and 'at-risk' populations. A systematic search identified all available randomised controlled trials (RCTs) of daily supplementation with ≥3 B group vitamins with an intervention period of at least four weeks. Random effects models for a standardized mean difference were used to test for overall effect. Heterogeneity was tested using the I2 statistic. Eighteen articles (16 trials, 2015 participants) were included, of which 12 were eligible for meta-analysis. Eleven of the 18 articles reported a positive effect for B vitamins over a placebo for overall mood or a facet of mood. Of the eight studies in 'at-risk' cohorts, five found a significant benefit to mood. Regarding individual facets of mood, B vitamin supplementation benefited stress (n = 958, SMD = 0.23, 95% CI = 0.02, 0.45, p = 0.03). A benefit to depressive symptoms did not reach significance (n = 568, SMD = 0.15, 95% CI = -0.01, 0.32, p = 0.07), and there was no effect on anxiety (n = 562, SMD = 0.03, 95% CI = -0.13, 0.20, p = 0.71). The review provides evidence for the benefit of B vitamin supplementation in healthy and at-risk populations for stress, but not for depressive symptoms or anxiety. B vitamin supplementation may particularly benefit populations who are at risk due to (1) poor nutrient status or (2) poor mood status.

Neurologic Manifestations of Vitamin B Deficiency after Bariatric Surgery.

INTRODUCTION: The aim of this study was to assess the incidence, clinical presentation, and outcomes of neurologic disorders secondary to vitamin B deficiencies following bariatric surgery. METHODS: Patients at a single academic institution who underwent bariatric surgery and developed neurologic complications secondary to low levels of vitamins B1, B2, B6, and B12 between the years 2004 and 2015 were studied. RESULTS: In total, 47 (0.7%) bariatric surgical patients (Roux-en-Y gastric bypass n = 36, sleeve gastrectomy n = 9, and duodenal switch n = 2) developed neurologic manifestations secondary to vitamin B deficiencies. Eleven (23%) patients developed postoperative anatomical complications contributed to poor oral intake. Median duration to onset of neurologic manifestation following surgery was 12 months (IQR, 5-32). Vitamin deficiencies reported in the cohort included B1 (n = 30), B2 (n = 1), B6 (n = 12), and B12 (n = 12) deficiency. The most common manifestations were paresthesia (n = 31), muscle weakness (n = 15), abnormal gait (n = 11), and polyneuropathy (n = 7). Four patients were diagnosed with Wernicke-Korsakoff syndrome (WKS) which was developed after gastric bypass (n = 3) and sleeve gastrectomy (n = 1). Seven patients required readmission for management of severe vitamin B deficiencies. Overall, resolution of neurologic symptoms with nutritional interventions and pharmacotherapy was noted in 40 patients (85%). The WKS was not reversible, and all four patients had residual mild ataxia and nystagmus at the last follow-up time. CONCLUSIONS: Nutritional neurologic disorders secondary to vitamin B deficiency are relatively uncommon after bariatric surgery. While neurologic disorders are reversible in most patients (85%) with vitamin replacements, persistent residual neurologic symptoms are common in patients with WKS.

Inositol-deficient food augments a behavioral effect of long-term lithium treatment mediated by inositol monophosphatase inhibition: an animal model with relevance for bipolar disorder.

Lithium treatment in rodents markedly enhances cholinergic agonists such as pilocarpine. This effect can be reversed in a stereospecific manner by administration of inositol, suggesting that the effect of lithium is caused by inositol monophosphatase inhibition and consequent inositol depletion. If so, inositol-deficient food would be expected to enhance lithium effects. Inositol-deficient food was prepared from inositol-free ingredients. Mice with a homozygote knockout of the inositol monophosphatase 1 gene unable to synthesize inositol endogenously and mimicking lithium-treated animals were fed this diet or a control diet. Lithium-treated wild-type animals were also treated with the inositol-deficient diet or control diet. Pilocarpine was administered after 1 week of treatment, and behavior including seizures was assessed using rating scale. Inositol-deficient food-treated animals, both lithium treated and with inositol monophosphatase 1 knockout, had significantly elevated cholinergic behavior rating and significantly increased or earlier seizures compared with the controls. The effect of inositol-deficient food supports the role of inositol depletion in the effects of lithium on pilocarpine-induced behavior. However, the relevance of this behavior to other more mood-related effects of lithium is not clear.

Low intake of B-vitamins is associated with poor adolescent mental health and behaviour.

OBJECTIVE: The current prevalence of mental health problems in Western populations is approximately 20% and half of all adult mental health disorders are estimated to originate in adolescence. Diet plays an important role in modulating psychological wellbeing and B-vitamins are vital for the synthesis of neurotransmitters such as serotonin. We aimed to examine the relationship between B-group vitamins and adolescent mental health and behaviour. METHODS: This is a cross-sectional analysis of the West Australian Pregnancy Cohort (Raine) Study. The 17-year follow-up included collection of a food frequency questionnaire allowing B-vitamin intake calculation. Mental health was assessed using the Youth Self Report (YSR) which measures total, internalising (withdrawn/depressed) and externalising (aggressive/delinquent) behaviour scores. Multiple linear regression was used to analyse associations between B-vitamins and mental health with adjustment for relevant confounders (n=709). RESULTS: Lower intake of vitamins B1, B2, B3, B5, B6, and folate was associated with higher externalising behaviour scores (p ≤ 0.05). Reduced intake of vitamin B6 and folate was associated with higher internalising behaviour scores (p ≤ 0.05). CONCLUSIONS: Poor nutrition may contribute to the pathogenesis of mental health problems in adolescence. The role of B-vitamins requires further investigation in randomised controlled trials.

Dietary methyl donor deficiency during pregnancy in rats shapes learning and anxiety in offspring.

Two important lines of research have enhanced our understanding of the molecular role of nutrition in influencing behavior. First, exposure to an adverse environment during early life can influence the long-term behavior of the offspring. Second, regulation of the nervous system development and functioning appears to involve epigenetic mechanisms that require a continuous supply of methyl group donors in food. We hypothesized that a maternal diet during pregnancy deficient in methyl donors (MDD) may lead to altered behavior in offspring through permanent changes in hippocampal DNA methylation. We used a rat model of prenatal dietary MDD to test this hypothesis in female offspring as they aged. Prenatal MDD reduced birth weight, litter size, and newborn viability. Aged female offspring of MDD mothers showed increased anxiety and increased learning ability in comparison with control diet group offspring. To explore the role of MDD on epigenetic mechanisms in the brain of adult offspring, we studied expression and methylation of 4 selected genes coding for glucocorticoid receptor, hydroxysteroid dehydrogenase 11 type 2, neuronatin, and reelin proteins in the hippocampus. No major group differences in methylation or expression of the studied genes were detected, except for a significant down-regulation of the reelin gene in the MDD female offspring. The prenatal MDD diet caused intrauterine growth restriction, associated with long-term effects on the behavior of the offspring. However, the observed behavioral differences between the MDD and control diet offspring cannot be explained by epigenetic regulation of the specific genes investigated in this study.

Dietary intake of B(6-9-12) vitamins, serum homocysteine levels and their association with depressive symptoms: the Zutphen Elderly Study.

OBJECTIVE: Low B-vitamin status and high levels of serum homocysteine are found in depressed inpatients, but results of population-based studies of this association are inconclusive. We investigated whether a low dietary intake of B(6-9-12) vitamins and high levels of serum homocysteine are associated with depressive symptoms in elderly men. METHODS: The study sample included a total of 332 men aged 70-90 years who were free from cardiovascular diseases and diabetes at baseline in 1990. Depressive symptoms were measured with the Zung Self-rating Depression Scale at baseline in 1990 and dietary factors with the crosscheck dietary history method in 1985 and 1990. Serum levels of homocysteine were obtained in 1985. Multiple linear and logistic regression analyses were performed. RESULTS: Dietary intake of folate (-1.19, 95% CI -2.03; -0.36) and vitamin B(6) (-2.09, 95% CI -2.92; -1.26) per standard deviation increase was associated with lower levels of serum homocysteine, while vitamin B(12) was not associated with serum homocysteine. Intake of folate, vitamin B(6), vitamin B(12) and levels of serum homocysteine were not related to depressive symptoms. CONCLUSIONS: Our results do not support the hypothesis that a low dietary intake of B(6-9-12) vitamins and high levels of serum homocysteine are related to depression in healthy elderly men.

Effects of a B-vitamin-deficient diet on exploratory activity, motor coordination, and spatial learning in young adult Balb/c mice.

Elevated homocysteine levels resulting from vitamin B deficiencies have been hypothesized to contribute to functional decline. To investigate the effects of elevated serum homocysteine on neurobehavioral performances, young adult Balb/c mice consumed a vitamin-B-deficient diet or a control diet under free-feeding and pair-fed conditions. The B-deficient diet decreased body weight and food intake but increased water ingestion. Relative to either control group, vitamin-B-deficient mice were more active in the open field and in enclosed arms of the elevated plus-maze. However, vitamin-B-deficient mice were not impaired on sensorimotor coordination and spatial learning tests, swimming to a visible platform even faster than either control group. The main effect of this diet restriction was hyperactivity with no change in anxiety, coordination, and memory. It remains to be determined whether severer deficits are demonstrable in older mice.

Mediterranean diet and depression.

OBJECTIVE: The adherence to a Mediterranean Dietary Pattern ensures an adequate intake of B vitamins and w-3 fatty acids. A protective role on depression has been suggested for both nutrients. DESIGN: Cross-sectional analysis from the SUN (Seguimiento Universidad de Navarra) prospective cohort study. Data from 9670 participants (4211 men and 5459 women) were analised. Logistic regression analyses were fitted to assess the association between B-vitamins and w-3 fatty acids intake (quintiles) and the prevalence of depression. RESULTS: Folate intake was inversely associated with depression prevalence among men, especially smokers. Among women, B12 vitamin intake was inversely associated with depression, especially among smokers and physically active women. No significant associations were observed for w-3 fatty acids intake. CONCLUSIONS: The adherence to a Mediterranean Dietary Pattern ensures an adequate intake of fruits, nuts, vegetables, cereals, legumes or fish, important sources of nutrients linked to depression prevention.